Ricin A-chain catalyzes the depurination of a single adenine base in mammalian 28S of intact ribosomes. The reaction destroys the binding site for eukaryotic initiation factors and therefore destroys ribosomal function. The reaction rate of the depurination of ribosomes is remarkable, at over 1500 per minute. The presence of a single ricin molecule in a eukaryotic cell is documented to result in cell death. Despite the presence of an X-ray crystal structure for ricin, the mechanism by which it catalyzes this remarkable reaction is obscure. A clue to its activity is that the region in which the adenine 4325 is excised predicts an RNA secondary structure of an RNA tetraloop. Support for this proposal is provided by the observation that small stem-loop structures, as small as 10 bases, are capable of being depurinated by ricin at the specific adenine, provided the essential loop structure, 5(-GAGA-3(, is present. Hydrolysis of the adenine is slow in these stem-loop structures, approximately 106 of that for the ribosomes. NMR structures of the RNA stem-loops show the succeptible adenine extruded from the base-paired stem region and freely accessible for the solvolysis by attack at the 1(-position of the ribosyl. This geometry is presumed to be essential for the ricin action. The hypothesis to be tested is that ricin A-chain acts as a poor catalyst for the stem-loop structures because binding of the RNA and the subsequent approach to the transition state configuration strains the stem region of the substrate stem-loop RNA, melts the stem, and permits the exposed adenine to internalize in the RNA structure where it is inaccessible to the enzyme. The RNA is then released in the stem-melted form to refold rapidly in the medium. This hypothesis will be tested by experiments to measure the rate of solvent deuterium exchange into base-paired RNA stem-loop structures which occurs more rapidly when the individual pairs are unfolded and unpaired.